Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm

J Clin Invest. 2014 Jun;124(6):2762-73. doi: 10.1172/JCI74182. Epub 2014 May 8.


Overactive RAS signaling is prevalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) in humans, and both are refractory to conventional chemotherapy. Conditional activation of a constitutively active oncogenic Nras (NrasG12D/G12D) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML-initiating cells, show strong hyperactivation of ERK1/2, promoting hyperproliferation and depletion of HSCs and expansion of downstream progenitors. Inhibition of the MEK pathway alone prolonged the presence of NrasG12D/G12D-expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of NrasG12D/G12D mice treated with MEK inhibitor alone died within 20 weeks, and the remaining animals continued to display JMML/MP-CMML-like phenotypes. In contrast, combined inhibition of MEK and JAK/STAT signaling, which is commonly hyperactivated in human and mouse CMML, potently inhibited human and mouse CMML cell growth in vitro, rescued mutant NrasG12D/G12D-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in NrasG12D/G12D animals. These results provide a strong rationale for further exploration of combined targeting of MEK/ERK and JAK/STAT in treating patients with JMML and MP-CMML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Genes, ras
  • Humans
  • Janus Kinases / antagonists & inhibitors*
  • Leukemia, Myelomonocytic, Chronic / drug therapy
  • Leukemia, Myelomonocytic, Chronic / enzymology
  • Leukemia, Myelomonocytic, Chronic / genetics
  • Leukemia, Myelomonocytic, Juvenile / drug therapy
  • Leukemia, Myelomonocytic, Juvenile / enzymology
  • Leukemia, Myelomonocytic, Juvenile / genetics
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Myeloproliferative Disorders / drug therapy*
  • Myeloproliferative Disorders / enzymology*
  • Myeloproliferative Disorders / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Signal Transduction / drug effects


  • Protein Kinase Inhibitors
  • Janus Kinases
  • Mitogen-Activated Protein Kinase Kinases